Interleukin 13
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| Location (UCSC) | n/a | Chr 11: 53.52 – 53.53 Mb | |||||||
| PubMed search | [2] | [3] | |||||||
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Interleukin 13 (IL-13) is a
Functions
IL-13 has effects on immune cells that are similar to those of the closely related cytokine IL-4.[4] However, IL-13 is suspected to be the central mediator of the physiologic changes induced by allergic inflammation in many tissues.[4]
Although IL-13 is associated primarily with the induction of airway disease, it also has anti-inflammatory properties.[4] IL-13 induces a class of protein-degrading enzymes, known as matrix metalloproteinases (MMPs), in the airways.[4] These enzymes are required to induce aggression of parenchymal inflammatory cells into the airway lumen, where they are then cleared.[4] Among other factors, IL-13 induces these MMPs as part of a mechanism that protects against excessive allergic inflammation that predisposes to asphyxiation.[4]
IL-13 is known to induce changes in
The signaling of IL-13 begins through a shared multi-subunit receptor with IL-4.[7] This receptor is a heterodimer receptor complex consisting of alpha IL-4 receptor (IL-4Rα) and alpha Interleukin-13 receptor (IL-13R1).[7] The high affinity of IL-13 to the IL-13R1 leads to their bond formation which further increase the probability of a heterodimer formation to IL-4R1 and the production of the type 2 IL-4 receptor. Heterodimerization activates both the STAT6 and the IRS.[7] STAT6 signaling is important in initiation of the allergic response.[7] Most of the biological effects of IL-13, like those of IL-4, are linked to a single transcription factor, signal transducer and activator of transcription 6 (STAT6).[7] Interleukin-13 and its associated receptors with α subunit of the IL-4 receptor (IL-4Rα) allows for the downstream activation of STAT6.[9] The JAK Janus kinase proteins on the cytoplasmic end of the receptors allows for the phosphorylation of STAT6, which then forms an activated homodimer and are transported to the nucleus.[9] Once, in the nucleus, STAT6 heterodimer molecule regulates gene expression of cell types critical to the balance between host immune defense and allergic inflammatory responses such as the development of Th2.[9] This can be resulted from an allergic reaction brought about when facing an Ala gene. IL-13 also binds to another receptor known as IL-13Rα2.[10] IL-13Rα2 (which is labelled as a decoy receptor) is derived from Th2 cells and is a pleotropic immune regulatory cytokine.[10] IL-13 has greater affinity (50-times) to IL-13Rα2 than to IL-13Ra1.[10] The IL-13Rα2 subunit binds only to IL-13 and it exists in both membrane-bound and soluble forms in mice.[10] A soluble form of IL-13Rα2 has not been detected in human subjects.[10] Studies of IL-13 transgenic mice lungs with IL-13Rα2 null loci indicated that IL-13Rα2 deficiency significantly augmented IL-13 or ovalbumin-induced pulmonary inflammation and remodeling.[10] Most normal cells, such as immune cells or endothelial cells, express very low or undetectable levels of IL-13 receptors.[10] Research has shown that cell-surface expression of IL-13Rα2 on human asthmatic airway fibroblasts was reduced compared with expression on normal control airway fibroblasts.[10] This supported the hypothesis that IL-13Rα2 is a negative regulator of IL-13–induced response and illustrated significantly reduced production of TGF-β1 and deposition of collagen in the lungs of mice.[10]
Interleukin-13 has a critical role in
Additionally, IL-13 has been shown to induce a potent fibrogenic program during the course of diverse diseases marked by elevated Type 2 cytokines such as chronic schistosomiasis and atopic dermatitis among others. It has been suggested that this fibrogenic program is critically dependent on direct IL-13 signaling through IL-4Rα on PDGFRβ+ fibroblasts.[12]
Evolution
IL-13 is closely related to IL-4, and both stimulate Type 2 immunity.[13] Genes of this family have also been found in fish, both in bony fish[14][15] and cartilaginous fish;[16] because at that evolutionary level they can't be distinguished as IL-4 or IL-13, they have been named IL-4/13.[15]
Clinical significance
IL-13 specifically induces physiological changes in
The eggs of the parasite
IL-13 expression has demonstrated to be increased in bronchoalveolar lavage (BAL) fluid and cells in patients with atopic mild asthma after allergen challenge.
Other research suggests that IL-13 is responsible for the promotion of the survival and the migration of epithelial cells, production of inducible nitric oxide synthase by airway epithelial cells, activation of macrophages, permeability of the epithelial cells, and transformation of airway fibroblasts to myofibroblasts leading to collagen deposition.[18] The deposition then influences the airway remodelling in asthmatic patients.[18]
Besides its well-established role in respiratory diseases IL-13 also plays a role in anti-inflammatory processes of other organs. It suppresses proinflammatory mediators and it is involved in wound repair after injury.[20] In type I diabetes, IL-13 antagonized cytotoxic insults to pancreatic β cells enhanced by IL-6.[21] In a mouse model of acetaminophen-induced liver injury eosinophil-driven IL-4/IL-13 mediated hepatoprotective function.[22] In severe alcohol-associated hepatitis low plasma level of IL-13 is a predictor of short-term (90-day) mortality.[23] However, in contrast to its short-term beneficiary effects in acute situations, chronically increased IL-13 contributes to development of fibrosis and cirrhosis.[24]
Dupilumab is a monoclonal antibody IL-13 and IL-4 modulator that targets the shared receptor of IL-4 and IL-13, IL4Rα.[25] Since IL-4 and IL-13 have similar biological activities, dupilumab may be an effective form of treatment for asthmatic patients.[25] Cendakimab is also a monoclonal antibody to the IL-13 receptor.[26]
See also
- Interleukin-13 receptor, the IL-13 receptor
References
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000020383 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ S2CID 4368915.
- PMID 8097324.
- PMID 1408833.
- ^ PMID 23283176.
- PMID 7907877.
- ^ PMID 24416647.
- ^ S2CID 30389002.
- ^ S2CID 23113468.
- PMID 27421703.
- PMID 26044597.
- PMID 17084456.
- ^ S2CID 24675205.
- S2CID 4447611.
- ^ PMID 26689873.
- ^ PMID 22951057.
- PMID 9856949.
- PMID 24527272.
- PMID 23510983.
- PMID 35714036.
- PMID 37994498.
- PMID 22510812.
- ^ PMID 25214796.
- PMID 35505944.
Further reading
- Marone G, Florio G, Petraroli A, de Paulis A (January 2001). "Dysregulation of the IgE/Fc epsilon RI network in HIV-1 infection". The Journal of Allergy and Clinical Immunology. 107 (1): 22–30. PMID 11149986.
- Marone G, Florio G, Triggiani M, Petraroli A, de Paulis A (2001). "Mechanisms of IgE elevation in HIV-1 infection". Critical Reviews in Immunology. 20 (6): 477–496. PMID 11396683.
- Skinnider BF, Kapp U, Mak TW (June 2002). "The role of interleukin 13 in classical Hodgkin lymphoma". Leukemia & Lymphoma. 43 (6): 1203–1210. S2CID 21083414.
- Izuhara K, Arima K, Yasunaga S (September 2002). "IL-4 and IL-13: their pathological roles in allergic diseases and their potential in developing new therapies". Current Drug Targets. Inflammation and Allergy. 1 (3): 263–269. PMID 14561191.
- Dessein A, Kouriba B, Eboumbou C, Dessein H, Argiro L, Marquet S, et al. (October 2004). "Interleukin-13 in the skin and interferon-gamma in the liver are key players in immune protection in human schistosomiasis". Immunological Reviews. 201: 180–190. S2CID 25378236.
- Copeland KF (December 2005). "Modulation of HIV-1 transcription by cytokines and chemokines". Mini Reviews in Medicinal Chemistry. 5 (12): 1093–1101. PMID 16375755.
External links
- Overview of all the structural information available in the PDB for UniProt: P35225 (Interleukin-13) at the PDBe-KB.
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